Small molecule antagonist probes for the relaxin-3/RXFP3 system

松弛素 3/RXFP3 系统的小分子拮抗剂探针

• 批准号: 10410553
• 负责人: JOYCE BESHEER
• 金额: $ 67.74万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410553
• 关键词: Acute; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Anxiety; Arousal; Attenuated; Behavior; Behavioral; Binding; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Cell Line; Cells; Chinese Hamster Ovary Cell; Chronic; Clinical; Complement; Computer Analysis; Cues; Cyclic AMP; Data; Development; Disease; Dose; Drug Kinetics; Eating; Evaluation; Family; G-Protein-Coupled Receptors; Goals; Homology Modeling; In Vitro; Injections; Knockout Mice; Lead; Ligands; Link; Locomotion; Messenger RNA; Metabolic; Modification; Motor Activity; Naltrexone; Names; Neuropeptides; Patients; Peptides; Peripheral; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Play; Property; Rattus; Relapse; Relaxin; Research; Role; Route; Self Administration; Series; Stress; Structure-Activity Relationship; Sucrose; System; Testing; Therapeutic; Therapeutic Agents; acamprosate; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol preferring rats; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcohol testing; alcohol use disorder; alcoholism therapy; analog; antagonist; base; behavioral phenotyping; behavioral study; biological adaptation to stress; design; hazardous drinking; high throughput screening; in silico; in vivo; inhibitor; intraperitoneal; medication compliance; new therapeutic target; novel; novel therapeutics; pharmacophore; preference; prevent; problem drinker; procedural memory; radioligand; receptor; scaffold; screening; side effect; small molecule; stress reduction; tool

The goal of this project is to develop and test small-molecule antagonist probes of the relaxin-3/RXFP3 system for behavioral studies in alcohol addiction and relapse. Alcohol addiction is a heterogeneous, chronic relapsing disorder. Current therapies are inadequate, and therefore new medications based on novel targets are needed. The recently deorphanized relaxin-3/RXFP3 system comprises the endogenous neuropeptide relaxin-3 and its cognate G protein-coupled receptor RXFP3. Multiple lines of evidence suggest that RXFP3 antagonism is a novel target for therapeutics to treat alcohol addiction and relapse. Although RXFP3 antagonist peptides are available, there are unmet needs for non-peptide small-molecule antagonists, which are systemically bioavailable and can penetrate the blood-brain barrier, to further validate the relaxin-3/RXFP3 system as a novel drug target. To date, our group has made significant progress in this regard. We have developed a stable RXFP3 cell-based cAMP high-throughput screening assay and completed a screening campaign to identify antagonist hits. Focused structure-activity relationship studies of the hit compound have resulted in the first series of small-molecule antagonists that have Ke <500 nM and are highly selective for RXFP3 over another receptor subtype RXFP1 and can penetrate into the brain. In this application, we propose to further refine our early lead-like compounds to produce antagonist probes for in vivo studies through three iterative specific aims. In Aim 1, we will optimize potency, receptor selectivity, and drug-like properties of RXFP3 antagonists using medicinal chemistry. In Aim 2, we will characterize compounds using an RXFP3 functional cAMP assay and a radioligand binding assay. Select compounds will be assessed for receptor selectivity against RXFP1 and RXFP4, two subtypes of the relaxin family, and further evaluated in a target profiling screen. Potent and selective compounds will then be characterized using a battery of ADME and pharmacokinetic assays. In Aim 3, we will test the best compounds, developed in Aims 1 and 2, in animal models of alcohol reinforcement and stress-induced reinstatement. Overall, completion of this project will provide in vivo antagonist probes to pharmacologically validate the relaxin-3/RXFP3 system as a novel target for treatment of alcoholism.

本项目的目标是开发和测试松弛蛋白-3/RXFP3系统的小分子拮抗剂探针。 用于酒精成瘾和复发的行为研究。酒精成瘾是一种异质性的慢性复发。 无序。目前的治疗方法是不够的，因此需要基于新靶点的新药物。 最近去变形的松弛蛋白-3/RXFP3系统由内源性神经肽松弛蛋白-3和它的 同源G蛋白偶联受体RXFP3。多条证据表明，RXFP3拮抗剂是一种 治疗酒精成瘾和复发的新靶点。尽管RXFP3拮抗剂多肽 目前，对非多肽小分子拮抗剂的需求还没有得到满足，这是系统性的 并且可以穿透血脑屏障，进一步验证Relacin-3/RXFP3系统是一种 新的药物靶点。迄今为止，我们小组在这方面取得了重大进展。我们已经开发出一种稳定的 RXFP3细胞为基础的cAMP高通量筛选试验，并完成了一次筛选活动，以确定 对抗性命中。Hit化合物的重点构效关系研究首次得到了 一系列具有KE&lt；500 nm的小分子拮抗剂，对RXFP3具有高度的选择性 受体亚型RXFP1，可穿透大脑。在此应用程序中，我们建议进一步完善我们的 早期类铅化合物通过三次迭代特异的方法生产用于体内研究的拮抗剂探针 目标。在目标1中，我们将优化RXFP3拮抗剂的效力、受体选择性和类药物特性 使用药物化学。在目标2中，我们将使用RXFP3功能cAMP分析来表征化合物 和放射性配基结合分析。将评估选定的化合物对RXFP1的受体选择性 和RXFP4，松弛蛋白家族的两个亚型，并在靶标分析筛选中进一步评估。强大而有力 然后，将使用一系列ADME和药代动力学分析对选择性化合物进行表征。在AIM 3，我们将测试在目标1和目标2中开发的最好的化合物，在酒精强化和 压力诱导的复职。总体而言，该项目的完成将提供体内拮抗剂探针 药理学验证松弛蛋白-3/RXFP3系统作为治疗酒精中毒的新靶点。

项目成果

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.

• DOI: 10.1021/acs.jmedchem.2c00508
• 发表时间: 2022-06-09
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Gay, Elaine A.;Guan, Dongliang;Van Voorhies, Kalynn;Vasukuttan, Vineetha;Mathews, Kelly M.;Besheer, Joyce;Jin, Chunyang
• 通讯作者: Jin, Chunyang